Gary Aston Jones: Treating Addiction With Dual Orexin Receptor Antagonists

Dr. Mark Leeds [00:00] Dr. Gary Aston-Jones, welcome to the podcast.

Gary Aston-Jones, PhD [00:03] Thank you, Mark. It’s nice to be here.

Dr. Mark Leeds [00:06] Thank you. So, yeah, so you are a brain expert, right? A brain expert at the Rutgers Brain Health Institute. Tell me a little bit about yourself and, you know, your expertise and, you know, and how in the brain and, you know, what kind of work you’re doing.

Gary Aston-Jones, PhD [00:24] Sure. Yeah, I got my PhD in neuroscience at Caltech and have studied systems in the brain for over 30 years now that are important in addiction, cognitive processes, and especially in motivation. Very interested in mechanisms that underlie motivated behavior, especially motivated behavior that is reward driven.

Dr. Mark Leeds [00:57] Okay. And now you said Caltech, that’s like, that’s where rocket scientists go to study.

Gary Aston-Jones, PhD [01:05] Yeah, they have, that’s where JPL is. And right, they have a lot of very strong programs. I was in the biology program there. They have a strong biology program as well. So yeah, I was very fortunate to be there. That’s where I really wanted to go and couldn’t believe it when I was able to. And it was a magical time. Richard Feynman was there when I was there. We’d see him hanging around, you know, and be able to talk to him and other people. John Wheeler, you know, would come through all these just luminary folks. So it was a very exciting time.

Dr. Mark Leeds [01:43] Yeah, that’s incredible. I love watching those videos of that most recent Mars rover landing, where the thing drops itself down on the surface and has to find its own landing place and everything. Those are really fun to watch.

Gary Aston-Jones, PhD [02:01] Yeah, they are. I had friends that were in the planetary sciences department there. One friend, Carolyn Porco, is really well known now. She led the Cassini imaging project to image Saturn. And she and I have been in communication and reliving old times. And we used to go rafting down the Colorado River and the middle fork of the Salmon River and just have a lot of fun together as graduate students. It was such a, like I said, an exciting time.

Dr. Mark Leeds [02:36] Oh, did you ever come in contact with Carl Sagan, the famous astronomer?

Gary Aston-Jones, PhD [02:41] I did not, but Carolyn won the Carl Sagan Award. Oh, wow. But no, I never met Carl.

Dr. Mark Leeds [02:51] Oh, okay. So yeah, let’s get back to the brain. And then the topic that we’re supposed to start with here, you were doing some research into some kind of a sleeping medication to help with addiction. And normally we try to avoid sleeping medications When people ask for a sleeping pill, you know, I’m like, oh, no, those are bad. You know, the Ambien and all the benzodiazepines, you know, they’re somehow neurotoxic, you know, especially the long term use. And I’m sure you know a lot more about that than I do. But I just know that they’re not good for, you know, maybe temporary, but even temporary short term use. We don’t want people to get too used to those things. But that’s not you’re working with some other kind of sleeping medication.

Gary Aston-Jones, PhD [03:33] Yeah, I am. I’m working with some newly developed sleeping medications. That work in an entirely different way from what’s called the Z drugs like Ambien, Zolpidem. Those drugs and benzodiazepines, the concern is they can be habit forming. And these newer drugs are based on a system in the brain that uses a neurotransmitter chemical called orexin, O-R-E-X-I-N. And that was a system discovered in 98. And then found in 99 to be very important in narcolepsy and in driving waking from sleep. Drug companies immediately started developing compounds to block signaling in this system with the idea that would then promote sleep and help treat insomnia by a very different mechanism from the Z drugs or benzodiazepines. And in fact, they do that. At the same time, we were doing studies in addiction, and we noticed that cells that make this orexin signaling transmitter were activated in situations where animals were looking for drugs. And that stimulated a lot of experiments by us and others that now consistently show that this orexin system is also very important in driving motivated responding for salient rewards, especially for drugs of abuse, very broadly across all classes of drugs of abuse. So cocaine, opioids, alcohol, nicotine, everything that’s been examined so far engages the system. And if we are able to block signaling in this system, we can block the hypermotivation that occurs in our animal experiments for different drugs of abuse. And there are recently results that indicate similar findings for human addiction patients as well.

Dr. Mark Leeds [05:36] Okay. And I hadn’t really heard much about this. I really nothing about this, to tell you the truth. How is it that, is this something that’s, do you think that this might be like a really significant effect that it might make the difference between someone going out to use more methamphetamine or cocaine or heroin or fentanyl? And if so, you would think this would be headlines splashed everywhere, like that everybody would be getting real excited that they can use this drug already out there. Maybe doctors could prescribe it off-label or whatever.

Gary Aston-Jones, PhD [06:11] Right. Doctors could prescribe it off-label, and I think they will. I think there will be also similar drugs developed for addiction. There are three drugs available right now that block signaling in orexin pathways from three different companies, Belsomra, Quviviq, and Dayvigo. So they all are blockers of orexin signaling. One, Belsomra, has been studied, I think, the most in human patients and in animal subjects as well. And even in humans, it’s shown to facilitate abstinence in a taper program where addicts will take less buprenorphine and be stable with less or no buprenorphine as long as they’re taking this Belsomra. So it’s consistent with a litany of animal experiments showing that if you block signaling in orexin, you can decrease this hypermotivation that is associated with stimuli that were previously associated with drugs of abuse and that drive a lot of the craving and drug seeking that occurs and lead to relapse in addiction subjects.

Dr. Mark Leeds [07:28] Yeah. And I’m actually looking up, I started looking at Belsomra and it says it is a control drug, Schedule 4. Does it have some abuse potential or is there any concern about that?

Gary Aston-Jones, PhD [07:43] You know, the FDA had concern about that. I think it’s misplaced. I think the reason they scheduled that and the other two as well, all of these drugs are Schedule 4 in the FDA is because they are sleep-inducing drugs. And so the FDA decided to schedule them just like they schedule Zolpidem and benzodiazepines, which is Schedule 4. And that was in the lack of evidence that it was a problem. I think it’s just being conservative on the part of the FDA. The companies certainly argued against that schedule, but how we’re not successful, our evidence indicates it’s not necessary, but yes, they are Schedule 4.

Dr. Mark Leeds [08:26] Okay. Yeah. And even the benzodiazepines apparently don’t have like a really high addictive potential. People tend not to even really get addicted. They become dependent on them.

Gary Aston-Jones, PhD [08:38] Right. That’s right. They become dependent. They become kind of habitually dependent. Also, if they stop abruptly, then there are repercussions when they suddenly terminate benzodiazepine administration. We don’t see that kind of thing with these orexin antagonist drugs. We don’t see a sort of rebound, for example, in any of our animal studies.

Dr. Mark Leeds [09:03] Okay. Now, you mentioned a person who might be opioid-dependent needing less buprenorphine or Suboxone. Does it in any way possibly help with the physical withdrawal syndrome that happens as a person takes less and less buprenorphine?

Gary Aston-Jones, PhD [09:20] Yeah, there’s also evidence that it works for that. An early paper, blanking on the author’s name right now, Ralph DiLeone, found that orexin antagonists are effective in decreasing withdrawal syndromes, again, in animal studies with opioids. That might be part of how they’re able to facilitate abstinence. But we see very marked effects in decreasing what we call demand for drugs. We use a behavioral economics paradigm that quantifies the amount of demand or motivation for drugs. And in the absence of withdrawal, we see very clear decreases in demand and motivation for drugs. So it might be that it acts in both ways. It decreases a motivation independent of withdrawal, but also attenuate withdrawal signs.

Dr. Mark Leeds [10:15] Okay. Yeah, that would be a major benefit because it’s not really a good exit plan for buprenorphine or suboxone.

Gary Aston-Jones, PhD [10:25] Absolutely right. No, those are opioid substitutions, right? That basically you’re taking an opioid to treat opioid addiction. And currently, there is no non-opioid therapeutic that’s effective for opioid use. And this would be the first real example of a mechanism completely aside from opioids that would attenuate opioid use. I think part of the reason that it’s not splashed in the headlines is because the companies are marketing these drugs to treat insomnia. That was the first finding, and that’s a bigger market, I think. And so they want to market them in that way. A lot of times companies don’t want to confuse their patient population with another indication, especially an indication like addiction, which has some negative connotations. I think the way it will move forward is the companies will develop other drugs that are very similar probably to the ones they now have for insomnia, but they’ll market them for addiction separately and they will turn out to be quite useful. It will require more clinical trials than have occurred so far. The clinical trials are very early days, so it’s going to take a few years of more clinical trials, but my prediction is these compounds will be found to be very useful for hypermotivation associated with abuse of a wide variety of drugs. And even for eating disorders, I think it will turn out to be useful because there’s a shared circuitry between eating disorders and drug abuse.

Dr. Mark Leeds [12:06] Yeah, I was just about to ask that. You actually jumped right into my next question. A huge addiction problem, food addiction, or maybe it’s carbohydrate addiction, binge eating. And there’s not really anything good for that. I think they’re using some diabetic drug for that. Naltrexone was combined with something else. I haven’t heard any really great results from any of these things. I mean, people keep binge eating and going to Weight Watchers and

Gary Aston-Jones, PhD [12:34] Overeaters Anonymous.

Dr. Mark Leeds [12:36] So do you think this might help people to eat less or binge eat less?

Gary Aston-Jones, PhD [12:42] I think that it might. That said, one caveat is Idorsia, who is the company that makes daridorexant, which is Quviviq, tried clinical trials for that orexin antagonist and binge eating disorder and didn’t find a signal. Animal studies do find a signal. And, you know, one issue might be being able to control the behavioral phenotype that you’re testing in animals compared to people. For example, it may work in animals, only in animals that are obese and have binge eating disorder, whereas in people, if you don’t select for a combination of those things, you may not pick up a signal. So I think, you know, it requires more study to identify the population that will be most responsive. There’s a lot there that we don’t quite understand, of course, in terms of mechanisms of actions of this system. But there’s quite a lot of animal studies that indicate it can be effective in BED, binge eating disorder models.

Dr. Mark Leeds [13:50] Okay. Yeah, that sounds great. Now, another group of people that are not, and they sometimes get confused with being addiction patients and they’re not, are people that are tapering off of, you know, mainly benzodiazepines and then also other psych drugs. But the, you know, the people with protracted withdrawal are taking, you know, you know, they’re often misguided and doctors mistreat them. They taper them far too quickly. And then they have a longer period of withdrawal or they taper very gradually. And, you know, and there’s just no good solution for them. They tend to be very sensitive to a lot of different medications and they don’t want to take more medication. But are you aware that this in any way might help someone, you know, maybe with the withdrawal symptoms? I mean, maybe even with the sleep issue because they can’t take, like you said, the Z drugs or the benzodiazepines, you know, those are things off limits to them. And maybe one of these drugs would help with their sleeping or insomnia and maybe with additionally withdrawal symptoms.

Gary Aston-Jones, PhD [14:51] That’s a very good point. I’m glad you brought that up because insomnia is a major comorbidity in all types of addiction. And the fact that these drugs treat insomnia well, I think is important in their ability to also treat addiction in those subjects. We have what we call the dual hit hypothesis. So we propose that the orexin antagonists like these drugs work in two ways. One is you might think of bottom-up, decreasing motivational drive for the drug in response to a stimulus that predicts drug availability. But the other way is by facilitating sleep. And you might think of that as having a top-down effect where that improves cognitive abilities. It improves executive function. And by improving executive function, that’s going to facilitate abstinence because that will make it less likely that the subject would continue taking drugs in the face of predicted negative consequences. You can sort of think about it more and be able to control your behavior better when you have better executive function. So I think it can work in both ways. And the sleep effect could be an important element.

Dr. Mark Leeds [16:06] Yeah, yeah, that makes sense. I mean, just being able to get to sleep. I mean, that’s people in early recovery. Sometimes they might go to their treatment program, they might go to meetings, and they get home and they’re kind of alone with themselves and they can’t fall asleep. And that’s a dangerous time.

Gary Aston-Jones, PhD [16:21] It is. Yeah, exactly right. Exactly so. And I agree that is one avenue that these drugs also can be beneficial.

Dr. Mark Leeds [16:30] Okay. Now, when you mentioned narcolepsy, right away I was thinking of there’s that other drug that does the opposite. I guess it helps people wake up, modafinil. Is there some relationship to how those two different drugs work? One wakes you up and one helps you fall asleep?

Gary Aston-Jones, PhD [16:48] Well, modafinil does stimulate orexin neurons. So the neurons that make this peptide, orexin, are responsive to modafinil. It activates them. And that might be one of the ways that modafinil drives waking. In narcolepsy, what’s interesting, though, is that narcoleptics, by and large, lack orexin neurons. So when studies were done initially in animals, people found that when they knocked out or eliminated the gene that makes orexin or the receptor for orexin, the animals exhibited narcoleptic-like symptoms. And that prompted people to look in the brains of human narcoleptic patients. And they discovered that they have almost no orexin neurons. And it seems like there’s an autoimmune disorder in narcolepsy often, narcolepsy cataplexy, that kills off the orexin neurons. And so the idea is you’re killing off these waking neurons, and that then drives sleep at inappropriate times, like you see in narcolepsy cataplexy. So the two could be related, but modafinil might work by activating the remaining neurons that haven’t been killed off by this autoimmune disorder. But, you know, that’s one of the lines of evidence that have strongly implicated orexin in sleep and wake control is this lack of these neurons in narcolepsy, cataplexy patients.

Dr. Mark Leeds [18:22] Okay. And are you current, like, what’s, is this what you’re, Are you working on specifically a research study right now with this? Can you tell us more about the specifics of that?

Gary Aston-Jones, PhD [18:35] Yeah, I’d be happy to. So we do animal studies and we train animals, for example, to self-administer fentanyl or cocaine. And what we have found recently is when animals go through a paradigm that makes them very strongly addicted to the drug, that actually increases the number of orexin neurons in their brains. So they have about 25 to 50% more orexin neurons when they go through a paradigm that makes them addicted. And it can be coke, it can be fentanyl, it can be oxycodone. All of these compounds or alcohol increase the number of orexin cells, which fits with this idea that the system is driving this hyper-motivated response. We recently published a paper that proposes that what’s happening is the orexin system normally can increase and decrease its expression adaptively. For example, there’s more expression in daytime and less expression of this peptide in nighttime. That’s one of the ways it regulates its signaling. But what happens with prolonged drug exposure and addiction is it gets stuck in the upstate. So there’s this what we call reserve population of orexin cells that turns on and doesn’t turn off like it normally would, but it stays on in a persistent fashion. So that it is that the system overall is larger in a sense when it responds to condition stimuli that predict drug availability and drives a bigger motivational response response than normal to, you know, salient stimuli. And these antagonists that are that important to sort of take that down a notch so that you lessen that hyper motivational response. But interestingly, you leave normal motivational activities in place. So that’s important, right? I mean, you don’t want to decrease all motivation for everything. You know, you can’t keep people eating and having sex and other kinds of drives. It seems like this orexin system really becomes aberrantly engaged with hypermotivation, and you can use these drugs to take the edge off, if you will, or decrease that hypermotivation, but still leave baseline motivational processes intact.

Dr. Mark Leeds [21:03] Okay. So if someone were to take one of these drugs, it probably is not going to take away all cravings and drive to use a drug, but maybe just enough to make it tolerable early on.

Gary Aston-Jones, PhD [21:15] Exactly. To help them, you could think of it almost like water wings when you’re learning to swim, right? I mean, it’s going to help them navigate the initial stages, especially of abstinence, and maybe even long-term help them remain abstinent by decreasing that hypermotivation that normally occurs when they encounter stimuli that previously have predicted drug availability. Now, that’s what happens with addicts. They will be in the environment, they’ll be abstinent, they’ll run into somebody or some situation where they previously took drugs, and that drives this craving response, in part because I think it’s activating the orexin system. And so by decreasing that larger drive than normal, I think they’re able to better navigate and remain abstinent.

Dr. Mark Leeds [22:10] Okay. I just had an interesting interview with someone that she’s an aromatherapist. As she was describing how that worked, I was thinking that this is definitely something that can’t hurt at all. I mean, why not? If it helps, you might as well offer it to anybody that has access to it. And this isn’t exactly the same because this is a real drug that has real side effects. But it does seem to be almost in that category of, you know, why not try it? You know, it’s not the same as Suboxone where a person, you know, you tell someone, we’re going to keep you on another opioid for a year or more and see how that goes. And that’s a big decision because they may want to try abstinence or some other kind of treatment. But this seems like a good adjunct therapy to other kinds of therapy.

Gary Aston-Jones, PhD [22:59] Absolutely agree. Suboxone doesn’t help the insomnia, right? Yeah. For example, and these drugs would. And so, yeah, I think it is well, these drugs are well suited for adjunct therapy, perhaps even for solo therapy in treating at least some types of addiction.

Dr. Mark Leeds [23:20] Yeah. Yeah. And yes, Suboxone actually wakes, keeps people awake. I have to tell people don’t take it too close to bedtime.

Gary Aston-Jones, PhD [23:27] Right. Exactly. Exactly.

Dr. Mark Leeds [23:31] Yeah. So what kind of animals do you use in the studies? Are they rats?

Gary Aston-Jones, PhD [23:35] Yeah. Yeah. We use rats, you know, and they have catheters that we implant in their jugular vein and they hit a little lever and they get a shot of coke or fentanyl. They quickly learn to hit the lever and that gives them IV drug, which they like and will work hard to obtain. We also give them light tones, condition stimulus that’s associated with those drugs. And those light tone stimuli by themselves will engage motivation that makes the animal work to find the drug. So we can measure drug seeking responses in this paradigm in response to those condition stimuli in that way, kind of mimicking what happens in a human addiction circumstance. And then we can manipulate systems in the brain. For example, if we decrease expression of orexin in animals, that decreases motivation as measured in our behavioral economics paradigm, very similar to giving them an antagonist like we’re now talking about. We can measure activity in these cells and see that they’re increased in association with the increased motivation for drugs. And we can see in animals that this increased expression of orexin is very persistent. So a rat will live about two years, 24 months. And if we make animals addicted and then just leave them alone, five months later, they still have this elevated number of orexin neurons and they still exhibit this high motivation for the drugs that they haven’t experienced in five months. So, again, that captures, I think, an important element in the addiction area where subjects are, in a way, you know, once you’re addicted, you’re always addicted, you know, that sort of rule. And I think that’s in some sense true and maybe in part because of this sustained change in the neurobiology of these orexin neurons. But now we have tools that allow us to manipulate and modulate, if you will, signaling in that system.

Dr. Mark Leeds [25:50] Yeah. Yeah. It seems like addiction is a really complicated thing. There’s a lot of different things involved. You know, you’re focusing on orexin and there’s a lot of talk about endorphins and opioid receptors. And, you know, there’s other, you know, I guess these different tracks in the brain or different areas of the brain, the, what is it, the anterior tegmental system and the nucleus accumbens, are those areas like related to this issue of the orexin neurons?

Gary Aston-Jones, PhD [26:19] Yeah, I think they are. The ventral tegmental area is a major dopamine signaling system in the brain, and dopamine has been found to be a sort of common denominator among all kinds of motivated behavior. Orexin has been found to strongly modulate activity in those dopamine neurons in the ventral tegmental area, and we think that one of the ways it works is by modulating those cells. So when orexin is present, it increases the response of dopamine cells to the condition stimuli that drives motivated responding. By tamping down the orexin input, we can decrease that hypermotivation, but leave the baseline motivation more intact because those cells are driven other ways as well as being modulated by the orexin system.

Dr. Mark Leeds [27:11] Okay. Yeah, that’s really interesting. And I have another question which might go completely outside of the orexin issue. But, you know, there’s, you know, in the use of opioid blockers like naltrexone long term, you know, people are concerned, you know, in the alcohol community, there’s a method where they call it the pharmacological extinction, you know, where they take naltrexone tablets when they drink. And then over time, the drive to consume alcohol goes down over time, they drink less and less. And then there’s people that follow that. They say, well, you know, we don’t want to block our endorphin system all the time. You know, we want to reinforce good behavior, but not reinforce bad behavior. And I was wondering if, is there any possibility that maybe that whole reward system is kind of like for humans, at least a vestigial thing that maybe we don’t even need it? Because there’s people that do take naltrexone for years and years and even have implants and have these receptors blocked and they seem to function fine. I mean, do we really need to have endorphins to tell us that’s a good berry to eat and that’s a bad one? Or is that more of like a caveman thing that we don’t need that anymore?

Gary Aston-Jones, PhD [28:23] Well, that’s an interesting question. I think, you know, like most parts of the brain and most systems in the brain, there’s more we don’t know than we do know. And a lot of systems like the endorphins are modulatory systems. They’re not, you know, driving a direct behavioral response. So you can take them away. And on the surface, it can look like they’re not having a major, you know, deleterious effect. But, you know, if you take it away long term, there might be effects that we haven’t studied yet. There might be effects, for example, on learning, on memory, other cognitive abilities like that, which, you know, motivation and reward are very important for learning and memory. You learn and remember things that are associated with reward. And so, you know, one wants to be careful about long-term manipulations of systems in the brain that we don’t understand all the aspects of. The naloxone treatment and that sort of pharmacological extinction study that you’re talking about is interesting. One of the issues with extinction, though, is when subjects learn extinction is learning a new relationship. It’s not forgetting the old relationship, right? So what they learn is when I take this drug, I no longer get the effect from it. But that has very little effect on some stimulus that was previously associated with them drinking, like going into a bar, and that stimulus driving a craving response to drink. So, you know, it’s a little tricky that way. And a lot of times those kinds of therapies are difficult to really implement in people, in real life situations, and longer term, there could be consequences that we’re not fully aware of yet.

Dr. Mark Leeds [30:27] Yeah, yeah, that makes sense. So it might be maybe a good idea, like when they say, let’s not take the drug every single day, only when we need it.

Gary Aston-Jones, PhD [30:40] Right. Yeah. I think that’s, you know, again, you know, that would be something clinical trials would be really informative about these orexin antagonists. First, let’s identify subjects that they’re likely to work well in. May not work for every case. And second, let’s examine when it makes sense to take the drugs. Maybe not every day, maybe not in every circumstance, but maybe in social situations where there’s a chance you might be exposed to stimuli that normally would drive a relapse response. You know, that’s possible that we can kind of tailor treatments around things like that after the initial period where you’re helping drive the initial abstinence. Then there might be more targeted therapeutic approaches like like that.

Dr. Mark Leeds [31:30] Yeah. And now what do you, have you studied or worked with these issues of, you know, protracted withdrawal? Like, you know, people who, you know, I talked about the, you know, people that consider themselves iatrogenically injured or injured by taking benzodiazepines and they feel that there’s some kind of a, you know, sometimes they call it toxic encephalopathy, that their brain has on some microscopic level been damaged, you know, damaged to resect. Receptors or changes, long-term changes in the brain. Does that sound reasonable that they’ve actually been, you know, not that there’s some big area of brain damage you can see on an MRI, but maybe something more subtle?

Gary Aston-Jones, PhD [32:10] Yeah, no, I think that’s certainly possible in the sense that even in our animal studies, like I was describing, we see very long-term effects of paradigms that make animals strongly addicted to drugs. And some of those long term, if we leave animals alone for five months, they show a very strong drive still for the drug. And we still see this elevated number of orexin neurons in the brain. Probably many other parts of the brain have persistent changes in gene expression as well that persist, that if we knew more about, we could start to think about therapeutics that would deal with those changes that have occurred that might be relatively permanent changes. You know, it raises a whole nother question. If these are long-term changes in brain physiology and function, what are the mechanisms underlying those long-term changes and how do we undo those long-term? Changes, right? Be it an epigenetic change or, and that’s very nascent research that we are really very new in the field, trying to understand the mechanism behind long-term changes in response to, for example, drugs of abuse. But certainly that happens. And, you know, whether it’s damage, you know, I don’t know that I would think of it necessarily in terms of damage, but If you think of it in terms of a change that’s occurred in the brain, probably in some kind of maladaptive way in response to prolonged exposure to these highly salient rewards.

Dr. Mark Leeds [33:56] Yeah. I had once heard, I don’t know where I heard this, something about, I guess, from long-term stimulant use, that the little sacs on a neuron that hold the neurotransmitters, that they can become leaky. Is that a real thing that happens? Or is that, maybe I’m not describing it correctly?

Gary Aston-Jones, PhD [34:13] Well, you’re probably thinking of vesicles that hold neurotransmitters and synaptic boutons and the degree to which they operate properly. Stimulants do cause release of dopamine from those vesicles. And prolonged stimulant administration does have effects on the ability of those vesicles to hold the dopamine and to reuptake the dopamine. Mean, for example, Rodrigo Andrade and others have looked at those kinds of effects in animal studies. So I think it could be a real thing. I don’t know that’s been established in people yet, but there are animal data consistent with that. And that might be another example of these sort of changes in brain that occur, you know, how persistent they are, how easily they are undone or how they could be treated pharmacologically is still an open question or an area of active research.

Dr. Mark Leeds [35:15] Okay. And I think one good thing, even if, you know, people listening to us are concerned about long-term brain damage, the good news is I think that brains are good at compensating and adjusting to changes and damage.

Gary Aston-Jones, PhD [35:29] Absolutely right. Absolutely right. You know, brains make new neurons all through adulthood in particular parts of the brain. Even aside from making new neurons, for example, these orexin cells can increase their expression of that neurotransmitter molecule and decrease that expression. They kind of wax and wane, usually adaptively. Something happens with prolonged drug exposure that gets them stuck in this upstate, the reserve orexin neurons continue making a lot of orexin. So it’s not damage, it’s a change. And knowing what that change is then opens the possibility for being able to reverse that change, as well as to give an antagonist that can block the effect of that elevated orexin signaling.

Dr. Mark Leeds [36:15] Okay, great. And another thing I was just curious, and this may be related or not, is that I had a discussion recently with someone that he provides ketamine therapy, and he was talking about stimulating the growth of dendrites. And I don’t know how significant that is. Are dendrites, are those the things that connect one neuron to many neurons, like one neuron can connect to maybe thousands of other neurons?

Gary Aston-Jones, PhD [36:44] Yeah, dendrites are the major receptive surface of neurons to receive input from other neurons. So they’re called dendritic trees. Dendrite is tree, right? That’s the word that means tree. So there are highly branched structures that emanate from a cell body of a neuron, and they receive lots and lots and lots of inputs, and they receive inputs from many different structures that way. And so increasing the number of dendrites increases the opportunity for those cells to be modulated more or less by the inputs from different areas. There are data in animal studies, again, that show in the nucleus accumbens that there are changes in dendrites during drug exposure that increases their receptivity to dopamine inputs from the VTA. And that’s one of the ways that the hyper-motivated responding occurs to drugs. But in turn, that dopamine input in the VTA, the ventral tegmental area, is regulated by orexin. So by blocking that orexin input, which increases activity in those cells, we can decrease signaling in that whole pathway, including the increased dendrites in the nucleus accumbens.

Dr. Mark Leeds [38:03] Okay. So just the act of growing more dendrites is not necessarily a positive thing that could work against us if they’re, you know, getting more of them in the wrong place.

Gary Aston-Jones, PhD [38:12] If they’re driving maladaptive behaviors, right? If they’re underlying the ability of cues associated with drugs to drive craving for the drug, then that’s not a good thing.

Dr. Mark Leeds [38:24] Okay. And that would imply, I think that therapy is very important, you know, or at least a person, you know, being aware and making positive changes in their life, you know, psychological things, rather than just worrying about the physical neuroanatomy.

Gary Aston-Jones, PhD [38:39] Absolutely agree. You know, I think that touches again on this top-down kind of element in the addiction process where increasing executive function increases top-down control over behavior and awareness of your problem and awareness of the negative consequences of your behaviors, I think can help you modulate your behavior and remain abstinent in a longer term. Increasing sleep is one way to increase that executive function, but therapy is another way that I think one could increase executive function in a beneficial way. Maybe a combination of, you know, of orexin antagonists with therapy could prove to be quite a strong approach.

Dr. Mark Leeds [39:31] Okay. Do you, of the three brands currently available of those sleep aid drugs for insomnia, if just say that, you know, a doctor has a patient to ask for, you know, just me, for example, say later today, a patient says, do you recommend something good for sleep? Could you give me a prescription for something? Do you have any reason to prefer one over the other?

Gary Aston-Jones, PhD [39:54] You know, it’s very early days. They’re all pretty recently approved drugs and have been relatively little studied in the addiction paradigm. Belsomra has probably been studied a little more in the addiction paradigm just because it was the first that was approved. But there’s no reason to think it would be better than Dayvigo or Quviviq. Yeah.

Dr. Mark Leeds [40:22] Yeah. I think you said it earlier. When was Belsomra approved?

Gary Aston-Jones, PhD [40:27] I believe it was 2014.

Dr. Mark Leeds [40:32] Oh, okay. Yeah, because somehow that name stands out more to me that, you know, I feel like there may have been like a company drug rep that came in and talked about it at some point.

Gary Aston-Jones, PhD [40:39] Yeah, that could be. It’s made by Merck. And I believe it was approved in 2014. And they’ve been marketing it recently on TV. You’ll see Quviviq. That just recently showed up in commercials on television. I’ve seen it recently to treat insomnia. And, you know, that’s made by Idorsia, which is a Swiss company. It’s quite a good drug, I think. You know, they have evidence that it has some advantages over Belsomra. But, you know, every company has evidence that their drug has advantages over other companies’ drugs. I think they’re all probably good drugs. And, you know, it may depend on the patient, you know, and the biomarkers, the kind of things that are driving them to an addiction profile might favor one over the other for a particular patient. But we don’t have the studies yet to really guide us well enough, I think, to choose among them at this point.

Dr. Mark Leeds [41:36] Okay. And so you’re currently, are you physically, are you at Rutgers in New Jersey?

Gary Aston-Jones, PhD [41:42] Currently, right now, I’m not, no. But that’s where my position is. That’s where I direct the Brain Health Institute. And that’s where my lab is, where my day job is. Experiments in animals and doing these self-administration and addiction studies.

Dr. Mark Leeds [42:00] Okay. Yeah, it seems like they, it might just be, there’s that really popular podcast by another brain scientist out of Stanford. So I don’t know, it seems like they must be doing a lot of brain research there also, or at least you hear about it a lot.

Gary Aston-Jones, PhD [42:15] Yeah, well, Stanford’s a very strong place in many sciences, including neuroscience. I’m not familiar with that podcast. I missed that one.

Dr. Mark Leeds [42:24] Oh, it’s Andrew Huberman. He’s really good. Yeah, you might want to look him up. He’s very easy to understand. So the public loves him, but he’s also a neuroscientist.

Gary Aston-Jones, PhD [42:35] Oh, I’ll look into him. Andrew Huberman. All right. Thanks for the tip.

Dr. Mark Leeds [42:40] Have you done any podcasting on your own?

Gary Aston-Jones, PhD [42:44] I have not.

Dr. Mark Leeds [42:46] Yeah, it’s fun.

Gary Aston-Jones, PhD [42:48] Yeah, it is. This is a very interesting, enjoyable conversation. You’re a great guide to it.

Dr. Mark Leeds [42:56] Oh, thank you. Thank you. Yeah, I love doing it. I love podcasting. I could never be a broadcaster. But yeah, I love asking questions, having conversations.

Gary Aston-Jones, PhD [43:07] Yeah, well, you ask a lot of good questions. And I think by asking questions and getting answers this way, it’s very informative to people. It’s like a Q&A session after a scientific talk, right? You get a lot of information out of that, a lot of times more than you did from the presentation itself.

Dr. Mark Leeds [43:26] Oh, definitely. Definitely. Do you teach undergraduate students at all?

Gary Aston-Jones, PhD [43:31] I don’t teach undergraduate students right now. I used to earlier in my career. But, you know, I’ve become more kind of administratively oriented and direct the Brain Health Institute with Rutgers. That includes over 300 neuroscience labs, 900 trainees. So that keeps us busy when we’re not in the lab doing experiments.

Dr. Mark Leeds [43:55] So what are some other interesting, notable experiments going on outside of, in your lab, under your direction?

Gary Aston-Jones, PhD [44:02] Well, the other major set of experiments that we’re doing involves another system in the brain called the locus coeruleus, which is a major norepinephrine system in the brain, also is involved in regulating sleep and waking. But our prior studies with that system show a role in attention and behavioral flexibility. So more executive function, cognitive sorts of processes. Disease. And it is implicated in many different disorders, including depression, sleep disorders, circadian disorders, and memory problems. It, for example, is one of the earliest pieces of the brain that degenerate during Alzheimer’s disease. In fact, it’s the earliest known place that starts to show damage during Alzheimer’s disease. So one would like to be able to manipulate these cells. The problem is they’re located right in the middle of your head, in between your ears. And so it would be quite invasive to go in and stimulate these neurons. We found recently a circuit that goes from the suprachiasmatic nucleus, which is an area in the brain that controls circadian rhythms, to the locus coeruleus, indirect circuit, goes through another part of the hypothalamus. The interesting thing about the suprachiasmatic is it gets its inputs mainly from the retina. And so that then opens up the possibility of regulating this locus ceruleus from the eye. And so we recently developed a method for doing that. We use what’s called chemogenetics, which is a way to insert a gene into retinal ganglion cells that then allows us with eye drops to stimulate those retinal ganglion cells, which in turn project to the suprachiasmatic and activate the locus coeruleus. And in our animal studies, that is effective in preventing or even reversing depressive-like behavior in response to different experiments. For example, light deprivation causes a depressive-like syndrome or stress. And also we recently have shown it’s effective in improving memory and behavioral flexibility in a genetic Alzheimer’s model in rats. So we’re very excited in driving that forward as a potential therapeutic in people. That approach I think is quite feasible in people. We have a patent on that and kind of working with venture capitalists and biotech companies to try to develop it as a therapeutic for treating a variety of neuropsychiatric disorders. So that’s the sort of other major project in my lab.

Dr. Mark Leeds [47:02] Oh, that’s incredible. And I know we definitely need more treatments for Alzheimer’s. I remember when I practiced in a much busier family medicine practice, it was terrible to see people decline with Alzheimer’s and very quickly. And it became a very difficult burden for the family members to take care of them. And then when the drug companies would come in and tell us about these different drugs, that none of them really, not only did they not reverse the symptoms, they didn’t even stop them. They slowed the decline, the rate of decline. It almost seemed like torture. It’s like, you’re going to go through this year of torture, but maybe we can stretch it out a little bit longer. And it became this moral dilemma, like, do we give these drugs or not? Because they’re not really going to do much to help. But yeah, it would be great if there was something much more effective.

Gary Aston-Jones, PhD [47:53] Yeah. Well, it’s early days. Again, these are only animal studies so far, but we see pronounced improvements in memory and behavioral flexibility in our genetic model of Alzheimer’s. It’s a treatment, not a cure, though. So it’s not preventing the damage that occurs, but it’s able to stimulate the remaining locus coeruleus neurons and compensate for the damage in locus coeruleus that happens in Alzheimer’s disease. And I think, you know, it could be a longer term treatment that might be effective over, you know, years of therapy, we’re hoping, but we need to do more studies to really map that out well.

Dr. Mark Leeds [48:37] Do you work with, I was thinking about this because somebody asked me to write an article about it and it was interesting. Transcranial magnetic stimulation. Is that useful to you or is that specific enough for your use?

Gary Aston-Jones, PhD [48:52] We don’t work with that. Typically, that is in either monkeys or people. There’s a little bit of TMS that’s done in rat, but it’s so available for study in people that a lot of times they just directly study it right in people, sometimes in monkeys. We haven’t done any of that, but it’s been found to be somewhat effective for some disorders in people. Some evidence for effectiveness in depression, as I remember, that’s the main one that I remember so far.

Dr. Mark Leeds [49:31] Yeah, apparently there’s like a deeper version. I guess like the deep one can get as deep as like four or five centimeters or something. And then that one, the deep TMS can work on OCD also, which I just learned this a couple of days ago.

Gary Aston-Jones, PhD [49:46] Yeah. Yeah. No, you know, these techniques are advancing quickly all the time with new methods to affect more areas in the brain and be able to triangulate and target deep brain structures, not just the surface structures. And so as they’re able to do that, they’ll be able to, you know, treat more disorders. That was part of the thing that we’re getting at with our retinal stimulation is being able to get to this deep brain system, which is a fundamental system for cognitive processes like attention and behavioral flexibility. Otherwise, it’s difficult to target.

Dr. Mark Leeds [50:22] Yeah, that’s incredible. So you’re actually changing a gene in the eye or something and creating a new photoreceptor somehow that goes.

Gary Aston-Jones, PhD [50:31] Well, actually, we insert a new gene into the eye that itself doesn’t do anything, but it’s a receptor for a particular compound that we can give, which itself is inert in the body. So it’s a sort of lock and key arrangement where you cause this gene to be expressed. It just sits there, doesn’t do anything. But you can give this drug, in our case, is an eye drop, which only affects those receptors. It doesn’t do anything else. So it’s a very selective, targeted, kind of targeted gene therapy approach, but different from other gene therapy approaches because you’re not affecting genes throughout the body. You’re only targeting these custom genes that you’ve engineered. These are engineered genes that you’ve caused to express in the eye. And then you target them with this engineered drug that selectively acts on those receptors.

Dr. Mark Leeds [51:29] Yeah, that’s incredible. So there’s definitely things to look forward to in the future. There’s definitely things in the works in the pipeline.

Gary Aston-Jones, PhD [51:35] Absolutely. That chemogenetic approach, even not necessarily in the eye, applied to other parts of the brain, I think will also turn out to be a very useful approach for neuropsychiatric disorders.

Dr. Mark Leeds [51:49] Okay. Thank you. Dr. Gary Aston-Jones, I want to thank you again. Thank you for joining me today on the podcast.

Gary Aston-Jones, PhD [51:56] Sure. Mark, it’s been great speaking with you. Thank you for having me.